α-Lipoic acid sensitizes lung cancer cells to chemotherapeutic agents and anoikis via integrin β1/β3 downregulation
α-Lipoic acid sensitizes lung cancer cells to chemotherapeutic agents and anoikis via integrin β1/β3 downregulation
复制标题
DOI：
10.3892/ijo.2016.3624
复制
发表时间：
2016-10-01
影响因子：
5.2
通讯作者：
Chanvorachote, Pithi
中科院分区：
文献类型：
--
作者：
Puchsaka, Punyawee;Chaotham, Chatchai;Chanvorachote, Pithi
化疗失败和转移是肺癌高死亡率的主要原因。内源性刺激或外源性化合物引起的细胞氧化还原状态的改变对细胞信号传导和行为具有显著影响。在此，我们首次透露，肺癌细胞暴露于α-硫辛酸（LA）会导致细胞内超氧阴离子（O-2（中心点-））和过氧化氢（H2 O2）水平升高，而这种特定活性氧物质（ROS）的增加下调了整合素β 1和β 3，这些整合素已知可增强侵袭行为和转移。LA处理的细胞在脱离条件下的存活能力和在锚定非依赖性软琼脂试验中的生长能力显著降低。此外，LA敏化顺铂，足叶乙甙和紫杉醇诱导的细胞凋亡。对于潜在的机制，我们发现用LA处理细胞显著降低整合素β 1和β 3，而对整合素α 5和α γ无影响。有趣的是，存活蛋白p-AKT和抗凋亡蛋白Bcl-2在与这种整合素调节的关联中减少。使用ROS探针和选择性抗氧化剂，我们已经表明，由LA诱导的H2 O2和O-2（中心点-）分别是β 1和β 3整合素减少的关键因素。这些发现表明LA以及特定ROS、O-2（中心点-）和H2 O2在整合素调节、失巢凋亡和化疗增敏中的新作用。
Chemotherapeutic failure and metastasis are the main causes of high mortality rate in lung cancer. Alteration of cellular redox status in response to endogenous stimuli or exogenous compounds has a significant impact on cell signaling and behavior. Herein we divulge for the first time that lung cancer cells exposed to a-lipoic acid (LA) resulted in a higher level of cellular superoxide anion (O-2(center dot-)) and hydrogen peroxide (H2O2), and such an increase of the specific reactive oxygen species (ROS) downregulated integrin beta 1 and beta 3, the integrins known for potentiating aggressive behavior and metastasis. The LA-treated cells exhibited significant decrease in their abilities to survive in detached condition and grow in anchorage-independent soft agar assay. Furthermore, LA sensitized the cells to cisplatin, etoposide and paclitaxel-induced apoptosis. For underlying mechanism, we found that the treatment of the cells with LA significantly decreased integrin beta 1 and beta 3, while had no effect on integrin alpha 5 and ay. Interestingly, survival protein p-AKT and anti-apoptotic protein Bcl-2 were reduced in an association to such integrin modulations. Using ROS probes and selective anti-oxidants, we have shown that H2O2 and O-2(center dot-) induced by LA are key players for the decrease of beta 1 and beta 3 integrins, respectively. These findings indicate a novel effect of LA as well as specific ROS, O-2(center dot-) and H2O2 in integrin regulation, anoikis and chemotherapeutic sensitizations.